Hellmann Expands on TMB Testing in Lung Cancer

Caroline Seymour

Published: Thursday, Apr 19, 2018

Matthew D. Hellmann, MD

PD-L1 and the recent emergence of tumor mutational burden (TMB) have helped guide physicians in selecting appropriate immunotherapy agents for patients with non–small cell lung cancer (NSCLC). Although the biomarkers are independent of each other, they have enabled practitioners to further predict the benefit of these therapies, explains Matthew D. Hellmann, MD.

An updated analysis of the CheckMate-586 study, which was presented during the 2018 AACR Annual Meeting, found that TMB identified patients who were more likely to derive a benefit from frontline combination immunotherapy with nivolumab (Opdivo) and ipilimumab (Yervoy).1 The study assessed the frontline combination for up to 2 years in patients with advanced NSCLC. The primary endpoint was overall response rate (ORR), stratified for patients with a PD-L1 expression less than or greater than 1%.

Results showed that the combination induced an ORR of 30%. Additionally, patients who presented with PD-L1 expression greater than 1% had an ORR of 41% versus 15% in those patients with less than 1% expression. Patients who were stratified by TMB showed response rates of 9% with TMB less than 5, 15% with TMB 5 to 10, 44% with TMB ≥10, and 39% for those with TMB levels of ≥15.

The implication of TMB on response rates was mirrored in the phase III results of the CheckMate-227 trial, in which the combination of nivolumab and ipilimumab more than tripled the 1-year progression-free survival (PFS) rate versus chemotherapy for treatment-naïve patients with NSCLC with high TMB.2,3 The 1-year PFS rate was 43% for patients with TMB ≥10 mutations/megabase treated with the immunotherapy combination versus 13% in those treated with platinum-doublet chemotherapy. The median PFS was 7.2 months versus 5.5 months, respectively. The investigators reported a significant reduction in risk of disease progression or death of 42% (HR, 0.58; 97.5% CI, 0.41-0.81; P <.001).

“Both of these biomarkers allow us to give immunotherapy to the right people and, in essence, avoid the toxicity of chemotherapy and have the opportunity for durable responses,” said Hellmann. “Should they need it, patients still have chemotherapy as a second-line therapy.”

In an interview during the 2018 OncLive® State of the Science Summit™ on Advanced Non–Small Cell Lung Cancer, Hellman, an assistant attending physician at Memorial Sloan Kettering Cancer Center, discussed the expansion of these biomarkers across single-agent and combination therapies in patients with NSCLC.

OncLive: Please provide an overview of your presentation at the meeting.

Hellmann: One of the things that was discussed was the progress we've made in understanding who best benefits from immunotherapy. We have known about the opportunity for immunotherapy and the possibility of long-term outcomes that are not possible with other treatments in lung cancer for a long time, and that’s really given patients hope. I have a handful of patients who are doing well years after they started immunotherapy. That possibility didn't exist prior to immunotherapy, so it's been a huge breakthrough. However, only a small fraction of patients who receive immunotherapy have an exceptional benefit.

It's important to understand who those patients are and how we can identify them beforehand—how we can predict who is the most likely to benefit from the therapy. The first biomarker that has come onto the clinical scene is PD-L1, based on studies such as KEYNOTE-024. PD-L1 has an important role in the management of patients with lung cancer and should be tested in all patients with lung cancer to determine whether frontline checkpoint inhibitor monotherapy is appropriate.

TMB is an emerging biomarker that is independent of PD-L1 and represents a new group of patients who can benefit from immunotherapy. We've made important progress in terms of identifying precision markers for use in immunotherapy.

Is TMB a predictive or prognostic factor?

When I first talked about TMB as a biomarker, it was largely in studies of patients in single-arm studies. People were uncertain about whether TMB was truly identifying predictive markers, or whether it was just identifying patients who happened to live longer.